1. Field of the Invention
This invention relates to a process for producing steroidal 7.alpha.-acylthio-4-en-3-ones. More particularly, this invention relates to a commercially practical process for producing steroidal 7.alpha.-acylthio-4-en-3-ones such as 7.alpha.-acetylthio-17-hydroxy-3-oxo-17.alpha.-pregn-4-ene-21-carboxylic acid .gamma.-lactone (hereinafter referred to as "spironolactone") which is a therapeutically effective antialdosteronic diuretic.
2. Description of the Prior Art
It is already known that the addition of a thiol or thiocarboxylic acid to an olefin can be accelerated with either light or a radical initiator such as a peroxide or azobisisobutyronitrile. For the addition of a thiocarboxylic acid to a steroidal 4,6-dien-3-one, however, such radical initiators have been found to exert little effect on acceleration of the reaction.
The above-mentioned spironolactone which is one of the steroidal 7.alpha.-acylthio-4-en-3-ones is usually prepared by reacting 17-hydroxy-3-oxo-17.alpha.-pregna-4,6-diene-21-carboxylic acid .gamma.-lactone with a large excess of thioacetic acid under heating. According to this procedure, the 7.beta.-acetylthio derivative which is therapeutically inactive is also produced as a by-product in approximately 25% yield, while the therapeutically active 7.alpha.-acetylthio derivative is obtained in a yield as low as 70%.
It is known from Japanese Patent Laying-Open Publication No. 4020/71 that the 7.alpha.-acetylthio derivative can be obtained in approximately 90% yield with methanol being used as a solvent but without the use of strong acid. In this procedure, however, 5 to 10% by-products are always formed in addition to the 7.alpha.- and 7.beta.-acetylthio derivatives and therefore it is impossible to obtain the desired 7.alpha.-acetylthio derivative in a yield exceeding 90%.
An article by Schaub et al., J. Org. Chem., 26, 3915-3925 (1961), discloses the formation of 7.alpha.-alkylthio and 7.alpha.-acylthio steroid hormone derivatives by addition to steroidal 4,6-dien-3-ones. Some examples showed the use of HCl in glacial acetic acid, but the yields were only moderate. The best yield was 61% for the formation of 7.alpha.-acetylthiotestosterone acetate.
A need therefore continues to exist for a method of forming steroidal 7.alpha.-acylthio-4-en-3-ones in high yield without formation of side products other than the epimeric 7.beta.-acylthio derivatives.